Interleukin-1β converting enzyme (ICE) acts on pro-interleukin-1β (pro-IL-1β) to produce interleukin-1β (IL-1β), an inflammatory cytokine. In fact, ICE (also known as Caspase-1) regulates at least four cytokines: ICE activates IL-1β and IL-18, and indirectly regulates the production of IL-1α and IFNγ.
Several diseases are associated with abnormal interleukin-1 activity. Examples of diseases in which interleukin-1 is involved include, but are not limited to, inflammatory diseases such as rheumatoid arthritis and inflammatory bowel disease, and neuroinflammatory disorders such as stroke. Other diseases in which interleukin-1 is involved include septic shock, reperfasion injury, Alzheimer's disease, and shigellosis.
Agents that modulate IL-1β activity have been shown to have beneficial effects in vivo. For example, compounds that are interleukin-1 receptor antagonists have been shown to inhibit ischaemic and excitotoxic damage in rat brains. See, e.g., Relton, J. K. et al., Brain Research Bulletin, 1992; 29:243-246. Additionally, ICE inhibitors have been shown to reduce inflammation and pyrexia in rats. See Elford, P R et al., British Journal of Pharmacology, 1995; 115:601-606.
In addition to its effects on IL-1β production, ICE has been shown to play a role in the production of the inflammatory mediator interferon-γ (Ghayur et al., Nature, 1997; 386(6625):619-623). ICE processes the inactive pro-interferon-γ inducing factor (pro-IGIF) to active IGIF (also known as Interleukin-18), a protein which induces production of interferon-γ by T-cells and natural killer cells. Interferon-γ has been implicated in the pathogenesis of diseases such as inflammatory disorders and septic shock. Therefore, ICE inhibitors should also have beneficial effects in certain disease states due to their effects on interferon-γ.
Recently, the nomenclature of the cysteine proteases in the ICE family (also known as Caspases with ICE being known as Caspase-1) has been further defined. According to the nomenclature described in Alnemri et al., Cell, 1996; 87:171, members of this class of enzymes are referred to as Caspase-2 (also known as Ich-1); Caspase-3 (also known as CPP32, Yama, and apopain); Caspase-4 (also known as TX, Ich-2, and ICE rel-II; Caspase-5 (also known as ICE rel-III); Caspase-6 (also known as Mch2); Caspase-7 (also known as Mch3); Caspase-8 (also known as FLICE and Mch5); Caspase-9 (also known as ICE-LAP6 and Mch6); and Caspase-10 (also known as Mch4).